chr7-97852296-C-T
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM5PP3PP5_Very_Strong
The NM_001673.5(ASNS):c.1649G>A(p.Arg550His) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R550C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001673.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASNS | NM_001673.5 | c.1649G>A | p.Arg550His | missense_variant | 13/13 | ENST00000394308.8 | |
CZ1P-ASNS | NR_147989.1 | n.3352G>A | non_coding_transcript_exon_variant | 19/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASNS | ENST00000394308.8 | c.1649G>A | p.Arg550His | missense_variant | 13/13 | 1 | NM_001673.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152156Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251354Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135842
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461824Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727206
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152274Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74448
ClinVar
Submissions by phenotype
Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitter | research | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
Likely pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Nov 15, 2018 | The homozygous p.Arg550His variant in ASNS was identified by our study in one individual with Asparagine Synthetase Deficiency. This variant has been identified in the literature in the case of one homozygous affected proband (Galada et al. 2018; PMID: 29405484). Another homozygous affected proband was reported in the literature (Faoucher et al. 2017). This variant has been identified in <0.01% (2/24030) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs552452349). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 23, 2020 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 04, 2020 | The alteration results in an amino acid change:_x000D_ _x000D_ The c.1649G>A (p.R550H) alteration is located in exon 14 (coding exon 11) of the ASNS gene. This alteration results from a G to A substitution at nucleotide position 1649, causing the arginine (R) at amino acid position 550 to be replaced by a histidine (H). The alteration is rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD) database, the ASNS c.1649G>A alteration was observed in 0.001% (3/282746) of total alleles studied, with a frequency of 0.008% (2/24964) in the African subpopulation. The alteration has been observed in affected individuals: _x000D_ _x000D_ This alteration has been reported in multiple affected individuals, including in the homozygous state as well as in trans with a second alteration in ASNS; commonly reported features include microcephaly, developmental delay, seizures, spasticity, and abnormal brain MRI including atrophy and simplified gyral pattern (Faoucher, 2017; Galada, 2018; Wang, 2020). Biochemical features showed low plasma asparagine level in two patients and low CSF asparagine level in one patient reported by Faoucher, et al. (2017)._x000D_ _x000D_ Additionally, an alteration at the same codon, c.1648C>T (p.R550C), has been observed in affected individuals, including in the homozygous state in two affected siblings with severe developmental delay, progressive microcephaly, axial hypotonia with appendicular hypertonia, hyperreflexia, hyperekplexia, and decreased cerebral volume and simplified gyri on brain MRI (Ruzzo, 2013) and in trans with a second alteration in two siblings with severe epileptic encephalopathy, gyral simplification, and microcephaly (Zillhardt, 2016). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.R550 amino acid is conserved in available vertebrate species. The alteration is predicted tolerated by in silico modeling:_x000D_ _x000D_ The p.R550H alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 25, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 550 of the ASNS protein (p.Arg550His). This variant is present in population databases (rs552452349, gnomAD 0.008%). This missense change has been observed in individuals with asparagine synthetase deficiency (PMID: 29405484, 32255274). ClinVar contains an entry for this variant (Variation ID: 800534). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ASNS protein function. This variant disrupts the p.Arg550 amino acid residue in ASNS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24139043, 27522229). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at